The Candidate: Matthew J. Pollman, M.D. has been trained in internal medicine and cardiology at the University of California San Francisco, Stanford University and currently the Brigham and Women's Hospital. He has been productive during his postdoctoral research training in molecular vascular biology in developing in vitro and in vivo models of vascular remodeling and has advanced the understanding of apoptosis regulation within the vasculature. The Proposal: As a natural extension of his research, under the mentorship of Gary H. Gibbons, M.D. and Robert D. Rosenberg, M.D., Ph.D., he proposes to use genetic and pharmacologic probes in both in vitro and in vivo model systems to define the role of PI-3 kinase, Akt and bcl-x as essential determinants of vascular smooth muscle cell (VSMC) survival. It is hypothesized that Akt is the distal link of a signaling pathway that couples extracellular stimuli to the regulation of cell fate by modulating the expression level and activity of bcl-X. The corollary to this working hypothesis poses that constitutive activation of Akt will render the VSMC resistant to apoptosis without influencing other cell fate determinations such as cell growth or differentiation. The specific objectives of the proposal include: I. Define the essential role of PI-3-kinase and Akt activation as mediators of an anti-apoptotic signal transduction cascade in VSMC. II. Define the effect of the anti-apoptotic signaling pathway mediated by PI-3 kinase-Akt on the expression and activity of the anti-apoptotic regulatory gene -- Bcl-xL. III. Develop novel mouse models of vascular remodeling using cell-specific gene targeting (i.e. SM-22-a promoter) to define the role of the anti-apoptotic mediators Akt and Bcl-xL as molecular determinants of VSMC fate in vivo. The Environment: The Brigham and Women's Hospital is a rich intellectual setting for nurturing young investigators. His primary mentor, Gary Gibbons and his co-mentor, Robert Rosenberg form the nucleus of his Advisory Committee additionally composed of Victor Dzau and Eva Neer who will provide mentoring guidance, valuable resources of equipment, technical expertise and scientific experience.